The LEDGF IBD–KMT2A grip: the second half of the clamp, and nobody is drugging it

[
  "KMT2A Phe129 (IBM1)",
  "KMT2A Phe148 (IBM2)",
  "KMT2A Leu149 (IBM2)",
  "KMT2A Phe151 (IBM2)"
]

[]

[
  "2MSR",
  "3U88",
  "2N3A",
  "2B4J",
  "3F9K",
  "3HPG",
  "6EMQ"
]

[
  {
    "pdb": "2MSR",
    "contents": "PSIP1 344-426 + KMT2A 140-160",
    "method": "NMR",
    "resolution_A": null,
    "pmid": "25082813",
    "title": "Validation and structural characterization of the LEDGF/p75-MLL interface as a new target for the treatment of MLL-dependent leukemia.",
    "authors": "Cermáková K, Tesina P, Demeulemeester J, et al.",
    "venue": "Cancer Res",
    "year": 2014,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  },
  {
    "pdb": "3U88",
    "contents": "MEN1 2-550 + KMT2A 103-153 + PSIP1 347-435",
    "method": "X-ray",
    "resolution_A": 3,
    "pmid": "22327296",
    "title": "The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.",
    "authors": "Huang J, Gurung B, Wan B, et al.",
    "venue": "Nature",
    "year": 2012,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  },
  {
    "pdb": "2N3A",
    "contents": "PSIP1 348-426 + POGZ 1389-1404",
    "method": "NMR",
    "resolution_A": null,
    "pmid": "26245978",
    "title": "Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif.",
    "authors": "Tesina P, Čermáková K, Hořejší M, et al.",
    "venue": "Nat Commun",
    "year": 2015,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  },
  {
    "pdb": "2B4J",
    "contents": "PSIP1 346-442 + HIV-1 integrase 1197-1359",
    "method": "X-ray",
    "resolution_A": 2.02,
    "pmid": "16260736",
    "title": "Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75.",
    "authors": "Cherepanov P, Ambrosio AL, Rahman S, et al.",
    "venue": "Proc Natl Acad Sci U S A",
    "year": 2005,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  },
  {
    "pdb": "3F9K",
    "contents": "PSIP1 347-435 + HIV-2 integrase",
    "method": "X-ray",
    "resolution_A": 3.2,
    "pmid": "19132083",
    "title": "A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75.",
    "authors": "Hare S, Shun MC, Gupta SS, et al.",
    "venue": "PLoS Pathog",
    "year": 2009,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  },
  {
    "pdb": "3HPG",
    "contents": "PSIP1 347-435 + visna virus integrase",
    "method": "X-ray",
    "resolution_A": 3.28,
    "pmid": "19609359",
    "title": "Structural basis for functional tetramerization of lentiviral integrase.",
    "authors": "Hare S, Di Nunzio F, Labeja A, et al.",
    "venue": "PLoS Pathog",
    "year": 2009,
    "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
  }
]

[
  "HIV-1 integrase",
  "POGZ",
  "JPO2 / CDCA7L",
  "MED19"
]

[]

[
  {
    "name": "CP65",
    "modality": "cyclic peptide",
    "effect": "selectively impairs clonogenic growth of primary murine MLL-AF9 blasts",
    "source_pmid": "25082813"
  },
  {
    "name": "LEDGIN class",
    "modality": "small molecule",
    "effect": "developed against the HIV-1 integrase-IBD interface; never tested against the KMT2A-IBD interface",
    "source": "ChEMBL CHEMBL3988590, best IC50 470 nM"
  }
]

[
  "2MSR is the LEDGF IBD with a KMT2A 140-160 peptide, not with menin; the ternary menin-KMT2A-LEDGF structure is 3U88",
  "3U88 comes from Huang et al. Nature 2012 (PMID 22327296), the same paper that reports menin-JUND; it is not from the Yokoyama and Cleary 2008 functional work",
  "No AlphaFold model exists for full-length KMT2A (AF-Q03164-F1 returns HTTP 404), so this interface cannot be modelled in the context of the whole protein"
]

{
  "_why": "Added by king sweep 2026-09-21 (Q82 corrections-owed #3). This entry quotes the menin-MBM1 53 nM figure. That number is NOT comparable to the KMT2A CXXC-DNA affinities without stating its buffer, and the omission is how a 1,300-fold 'discrepancy' was manufactured.",
  "value": "53 nM",
  "motif": "KMT2A MBM1, residues 4-15, FITC-labelled peptide at 15 nM",
  "method": "fluorescence polarisation",
  "buffer": "50 mM Tris, pH 7.5, 50 mM NaCl, 1 mM DTT",
  "nacl_mM": 50,
  "companion_itc": "72 nM by ITC, 50 mM phosphate pH 7.5, 50 mM NaCl, 1 mM beta-mercaptoethanol, 27 C",
  "source_pmid": "20961854",
  "source_quote": "\"in the FP buffer (50 mM Tris, pH 7.5, 50 mM NaCl, 1 mM DTT) used for binding experiments (Kd measurements)\" -- Grembecka 2010 JBC, Methods, fetched and read from PMC3003368 on 2026-09-21",
  "do_not_compare_naively": {
    "against": "KMT2A CXXC-DNA Kd 44 uM (PMID 20010842, Cierpicki 2010)",
    "because": "that measurement was made at 300 mM NaCl -- verbatim from its Methods, \"50 mM phosphate buffer (pH 7.1), 300 mM NaCl, 2 mM DTT at 25 C\" (PMC2908503, read 2026-09-21) -- SIX-FOLD more salt, on a salt-sensitive protein-DNA contact, against a hydrophobic peptide pocket that is not.",
    "best_matched_pair": "44 uM at 300 mM NaCl vs the 5.7 uM tagless CXXC measurement at 150 mM NaCl gives 108-fold against menin, not ~1,000-fold",
    "see": "ana-the-menin-affinity-comparison-was-made-at-one-sixth-the-salt"
  },
  "added": "2026-09-21"
}

{
  "_why": "Added by king sweep 2026-09-21 (cycle 46). This entry quotes the KMT2A CXXC-DNA 44 uM. That number is a property of five choices, not of the molecule, and quoting it bare is how this graph manufactured a 1,300-fold 'discrepancy' with the menin contact.",
  "value": "44 uM",
  "construct": "isolated CXXC domain, KMT2A 1147-1203, untagged, 15N-labelled",
  "ligand": "DNA pal oligonucleotide, one CpG element",
  "method": "NMR titration",
  "buffer": "50 mM phosphate, pH 7.1, 300 mM NaCl, 2 mM DTT, 25 C",
  "nacl_mM": 300,
  "source_pmid": "20010842",
  "source_quote": "\"Determination of the dissociation constants by NMR for the CXXC domain (MLL 1147-1203) and mutants was performed by titration of 15N-labeled protein with concentrated solutions of DNA pal oligonucleotide. Experiments were carried out in 50 mM phosphate buffer (pH 7.1), 300 mM NaCl, 2 mM DTT at 25 C.\" -- Cierpicki 2010 NSMB, Methods, fetched and read from PMC2908503 on 2026-09-21. The result sentence reads \"The wild type protein yielded a Kd of 44 uM\".",
  "this_is_the_high_salt_end": "300 mM NaCl is roughly twice physiological ionic strength and SIX TIMES the 50 mM the menin-MBM1 53 nM was measured in. The same domain measured tagless at 150 mM NaCl gives 5.7 uM -- 7.7-fold tighter from salt alone.",
  "do_not_compare_naively": {
    "against": "menin-MBM1 53 nM (PMID 20961854), measured at 50 mM NaCl by FP",
    "best_matched_pair": "108-fold, not ~1,000-fold",
    "see": "ana-the-menin-affinity-comparison-was-made-at-one-sixth-the-salt"
  },
  "added": "2026-09-21"
}